Encorafenib (1) – Braftovi®

• Clinical trials
  • The COLUMBUS study is a randomised, open-label, actively controlled, multicentre, three-arm Phase III trial.
  • The coBRIM study is a randomised, double-blind, actively controlled, multicentre, two-arm Phase III study.

a) Adult, treatment-naïve patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation

• For untreated patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation, additional benefit is not proven.
• mortality
  • For the endpoint of overall survival, there is no statistically significant difference between encorafenib in combination with binimetinib and vemurafenib in combination with cobimetinib (hazard ratio: 0.87 [0.60; 1.24], p-value = n/a). An additional benefit of encorafenib in combination with binimetinib compared with vemurafenib in combination with cobimetinib is therefore not proven for overall survival.
• morbidity
  • No statistically significant difference was observed for the progression-free survival (PFS) endpoint (hazard ratio: 0.81 [0.57; 1.13], p-value = n/a).
  • The data presented on patient-reported endpoints in the categories of morbidity and health-related quality of life are considered unusable due to differences in data collection strategies between the COLUMBUS and coBRIM studies.
  • Owing to the differing data collection strategies in the COLUMBUS and coBRIM studies and their unclear implications, the data on disease symptoms are, on the whole, considered unusable in the context of an indirect comparison.
  • The limitations of the data relating to the assessment of disease symptoms, which stem from differing measurement strategies in the COLUMBUS and coBRIM studies, apply equally to the assessment of health status.
• quality of life
  • The limitations of the data mentioned in connection with the collection of disease symptoms, due to differing measurement strategies in the COLUMBUS and coBRIM studies, apply equally to the collection of health-related quality of life data.
  • Consequently, the results on health-related quality of life are considered unusable, in line with the explanations given in the ‘Symptoms’ section.
• Side effects
  • Differences are evident between the bridging arms of the COLUMBUS and coBRIM studies with regard to endpoints in the ‘Side effects’ category.
  • In the COLUMBUS study, higher rates of events were observed in the vemurafenib arm for all endpoints relating to side effects than in the bridging arm of the coBRIM study.
  • There are significant uncertainties regarding side effects. This is partly due to differences in study conduct regarding continued treatment with vemurafenib following progression, and partly due to the high proportion of potentially informative censorings for the endpoints SAE and severe AEs (CTCAE grade ≥ 3).
  • Furthermore, there is uncertainty regarding the endpoint ‘discontinuation due to AEs’ owing to the open-label design of the COLUMBUS trial, in contrast to the coBRIM trial.
  • Further uncertainties arise from the incomplete data on specific side effects.
  • In summary, it must be noted that there are significant uncertainties regarding side effects, meaning that an assessment of adverse events is not possible on the basis of the indirect comparison presented.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of encorafenib in combination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, results are available on mortality, morbidity, quality of life and side effects compared with vemurafenib in combination with cobimetinib.
  • Based on the indirect comparison, only the results on mortality are sufficiently meaningful.
  • In the overall assessment of side effects, it is therefore not possible to evaluate adverse events on the basis of the indirect comparison.
  • An additional benefit of encorafenib in combination with binimetinib compared with vemurafenib in combination with cobimetinib for the treatment of treatment-naivous patients with unresectable or metastatic melanoma with a BRAF V600 mutation is not proven.

b) Adult, previously treated patients with unresectable or metastatic melanoma with a BRAF V600 mutation

• An additional benefit is not proven for previously treated patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
• No relevant data were submitted for the assessment of the additional benefit of encorafenib in combination with binimetinib compared with the appropriate comparator therapy in pre-treated patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation.

Courtesy translation only, please refer to the German original.